A Wnt-producing niche drives proliferative potential and progression in lung adenocarcinoma.
A Wnt-producing niche drives proliferative potential and progression in lung adenocarcinoma.
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DOI：
10.1038/nature22334
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发表时间：
2017-05-18
期刊：
影响因子：
64.8
通讯作者：
Jacks T
中科院分区：
文献类型：
--
作者：
Tammela T;Sanchez-Rivera FJ;Cetinbas NM;Wu K;Joshi NS;Helenius K;Park Y;Azimi R;Kerper NR;Wesselhoeft RA;Gu X;Schmidt L;Cornwall-Brady M;Yilmaz ÖH;Xue W;Katajisto P;Bhutkar A;Jacks T
癌症中细胞状态的异质性与耐药性、癌症进展以及具有正常组织干细胞特性的癌细胞的存在有关。分泌的 Wnt 信号维持各种上皮组织中的干细胞，包括肺发育和再生。在这里，我们报道小鼠和人类肺腺癌显示出具有两个不同亚群的分层特征，一个亚群具有高Wnt信号传导活性，另一个形成提供Wnt配体的生态位。 Wnt应答细胞表现出增强的肿瘤增殖能力，表明它们具有正常组织干细胞的特征。 Wnt 产生或信号传导的遗传扰动抑制了肿瘤进展。针对 Wnt 重要翻译后修饰的小分子抑制剂可减少肿瘤生长，并显着降低肺癌细胞的增殖潜力，从而提高荷瘤小鼠的生存率。这些结果表明，破坏维持干细胞样和生态位细胞表型的途径的策略可以转化为有效的抗癌疗法。
The heterogeneity of cellular states in cancer has been linked to drug resistance, cancer progression and presence of cancer cells with properties of normal tissue stem cells. Secreted Wnt signals maintain stem cells in various epithelial tissues, including in lung development and regeneration. Here we report that murine and human lung adenocarcinomas display hierarchical features with two distinct subpopulations, one with high Wnt signaling activity and another forming a niche that provides the Wnt ligand. The Wnt responder cells showed increased tumour propagation ability, suggesting that they have features of normal tissue stem cells. Genetic perturbation of Wnt production or signaling suppressed tumour progression. Small molecule inhibitors targeting essential post-translational modification of Wnt reduced tumour growth and dramatically decreased proliferative potential of the lung cancer cells, leading to improved survival of tumour-bearing mice. These results indicate that strategies for disrupting pathways that maintain stem-like and niche cell phenotypes can translate into effective anti-cancer therapies.
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影响因子：
3.7
作者：
Fuerer C;Nusse R
通讯作者：
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影响因子：
64.8
作者：
Konermann S;Brigham MD;Trevino AE;Joung J;Abudayyeh OO;Barcena C;Hsu PD;Habib N;Gootenberg JS;Nishimasu H;Nureki O;Zhang F
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通讯作者：
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64.5
作者：
Hsu PD;Lander ES;Zhang F
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